Kidney Week

Abstract: FR-OR11

Intracellular Magnesium Trafficking: A Novel Target to Prevent Ischemic Kidney Injury

Session Information

• AKI Research: Mechanisms
  November 04, 2022 | Location: W230, Orange County Convention Center‚ West Building
  Abstract Time: 04:30 PM - 04:39 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Reeves, William Brian, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

William Brian Reeves, MD, FASN

• Wang, Weiwei, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Weiwei Wang,

• Li, Kang, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Kang Li,

• Kim, Serena Jiyeon, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Serena Jiyeon Kim,

• Venkatesan, Manigandan, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Manigandan Venkatesan,

• Vishnu, Neelanjan, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Neelanjan Vishnu,

• Ramachandran, Karthik, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Karthik Ramachandran,

• Madesh, Muniswamy, The University of Texas Health Science Center at San Antonio Joe R and Teresa Lozano Long School of Medicine, San Antonio, Texas, United States

Muniswamy Madesh,

Background

Mitochondrial dysfunction is a hallmark of AKI. We recently reported that intracellular lactate triggers the release of Mg²⁺ from endoplasmic reticulum with subsequent Mg²⁺uptake by mitochondria via the mitochondrial Mg²⁺ channel Mrs2 (Daw et al Cell 2020). High mitochondrial Mg²⁺ uptake resulted in impaired mitochondrial function. Since lactate accumulation occurs in conditions of impaired oxidative phosphorylation, we explored the role of mitochondrial Mg²⁺ uptake in ischemic AKI.

Methods

We induced ischemic AKI via bilateral clamping of the renal pedicle for 26 minutes in male WT mice and in mice lacking Mrs2 (Mrs2 KO). Kidney function was assessed by measurement of blood urea nitrogen (BUN) and creatinine. Kidney histology was assessed by PAS staining and Ly6G staining for neutrophils.

Results

WT mice developed severe loss of renal function (24 hr BUN=99+16 mg/dl, Cr= 1.13+.19 mg/dl, n=9), along with elevated KIM1 and NGAL, histologic tubular injury and leukocyte infiltration. In contrast, Mrs2 KO mice had preserved renal function (BUN=27+7 mg/dl, creatinine=0.48+0.09 mg/dl, n=9, P<0.01 vs WT) and less histologic damage and inflammation. Studies in bone marrow chimeric mice demonstrated that the presence or absence of parenchymal Mrs2, rather than hematopoietic Mrs2, accounted for these differences. CPACC, a novel inhibitor of Mrs2, administered 2 hours prior to ischemia largely prevented ischemic kidney injury (Cr: CPACC 0.35+0.06 mg/dl vs saline 1.47+0.30, P=0.006, n=5). To explore the potential role of lactate in mediating these effects, we administered oxamate, an inhibitor of LDH, which catalyzes the conversion of pyruvate to lactate, prior to ischemia. Mice which received oxamate, sustained significantly less renal dysfunction (BUN 34+5 mg/dl; Cr 0.37+.06 mg/dl), histologic injury and inflammation than saline treated mice (BUN 148+25 mg/dl, Cr 0.93+0.12 mg/dl, P=0.0001). Administration of oxamate 6 hours after ischemia had no protective effect.

Conclusion

These results support the view that lactate-triggered Mg²⁺ uptake into mitochondria is a critical mediator of ischemic AKI and that targeting this pathway may prevent ischemic kidney injury.

Funding

• NIDDK Support